So far several methods of preparation of zileuton of formula I have been described that are contained in patents.    Method (a): (U.S. Pat. No. 4,873,259) Reaction of 2-acetylbenzo[b]thiophene of formula IV with hydroxylamine producing the oxime of formula V, which should produce the corresponding hydroxylamine of formula VI through reduction by the borane-pyridine complex. The substance of formula VI is then transformed to zileuton of formula I through a reaction either with cyanic acid or trimethylsilyl isocyanate (Scheme 1).
    Method (b): (U.S. Pat. No. 4,873,259) Substitution of 1-(benzo[b]thien-2-yl)-1-chloroethane of formula VII with hydroxylamine producing the substance of formula VI, followed by addition to cyanic acid or trimethylsilyl isocyanate (Scheme 2).

A disadvantage of the above mentioned preparation methods a) and b) is that even by carefully reproducing these methods we did not manage to prepare zileuton.    Method (c): (U.S. Pat. No. 6,080,874) Coupling of 1-(benzo[b]thien-2-yl)-ethanol of formula II with hydroxycarbamide of formula III in an organic solvent in the presence of acids such as hydrochloric, sulphuric, trifluoroacetic and tuloenesulfonic acid (Scheme 3).

A reproduction of this method provided relatively acceptable results; however, even here some problems were encountered. One of them is high laboriousness of product isolation from the reaction mixture and the resulting relatively low purity and low yield of obtained zileuton. American U.S. Pat. No. 6,080,874 describes general use of acids as the reaction environment. However, when examining this procedure we have found out that the reaction was considerably more complex and the use of acids was not as general as described. The reaction takes place in hydrochloric acid or some other above mentioned acids, but does not take place, or just traces of the product are generated, in case a number of other acids are used, mainly organic acids, e.g. acetic or propionic acid. Also, reactivity is not just the question of pH—e.g. the reaction does not take place if citric acid with pKa of 3.14 or oxalic acid with pKa of 1.25 is used.
The procedure described in U.S. Pat. No. 6,080,874 is laborious and feasible with difficulties; the product is isolated in low yields and with a relatively high content of impurities.